It is currently believed that vitamin A, retinol, is biologically inert and that its myriad of biological functions are exerted by active metabolites: the visual chromophore 11-cis-retinaldehyde, and retinoic acids, which regulate gene expression by activating specific nuclear hormone receptors. Surprisingly, our preliminary data suggest that retinol is a transcriptional regulator in its own right. Retinol circulates in blood bound to serum retinol- binding protein (RBP) but it must dissociate from the protein prior to entering target cells. It was recently shown that an integral plasma membrane protein termed STRA6 binds RBP and mediates the uptake of retinol into cells. Our preliminary results demonstrate however that, in addition to its function as a vitamin A transporter, STRA6 is a ligand-activated cell surface receptor which activates a JAK/STAT pathway in response to binding retinol-RBP. Specifically, the data indicate that, association of STRA6 with retinol-bound RBP results in phosphorylation and activation of STATs, which, in turn, induce the transcription of specific STAT target genes. Studies proposed here will address the hypothesis that retinol can regulate gene transcription by activating a signalling pathway mediated by an RBP/STRA6/STAT pathway. We further propose to elucidate its involvement of this pathway in regulation of lipid homeostasis and insulin responses and in control of cell growth and survival. The results of these studies may point at novel targets for therapeutic approaches in treatment of diabetes and cancer. PUBLIC HEALTH RELEVANCE: Insulin resistance and diabetes are global public health problems of epidemic proportions and there is an urgent need for elucidating the molecular basis of these diseases and for identifying novel therapeutic targets. Vitamin A (retinol) is present in blood bound to a protein termed retinol binding protein (RBP) and is taken up from this protein into target cells by a transporter called STRA6. It was recently suggested that RBP is a causative factor in the induction of insulin resistance but it is unknown how the protein may exert such an effect. A mechanism through which RBP inhibits insulin action is suggested by our preliminary observations. These data show that binding of vitamin A-bound RBP to STRA6 results in activation of a signalling cascade that culminates in upregulation of the expression of genes that inhibit insulin signalling. The findings thus indicate that vitamin A possesses a previously unsuspected function in regulation of gene expression. Proposed studies will examine the involvement of the novel activity of vitamin A in regulation lipid metabolism and insulin sensitivity as well as in control of cell growth and survival. The results of these studies may point at novel targets for therapeutic approaches in treatment of diabetes and cancer.